The present invention relates to novel sulfonyl pyridazinone compounds, pharmaceutical compositions comprising those compounds and to methods of using such compounds and compositions to inhibit aldose reductase, lower sorbitol levels and, thus, lower fructose levels, and/or treat or prevent diabetic complications such as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic microangiopathy and diabetic macroangiopathy in mammals. This invention also relates to pharmaceutical compositions and kits comprising a combination of an aldose reductase inhibitor (ARI) of Formula I herein and a sorbitol dehydrogenase inhibitor and to methods of using such compositions or kits to treat or prevent the above diabetic complications in mammals. This invention also relates to other combinations with the ARIs of Formula I, including combinations with NHE-1 inhibitors; adenosine agonists; glycogen phosphorylase inhibitors (GPIs); selective serotonin reuptake inhibitors (SSRIs); xcex3-amino-butyric acid (GABA) agonists; antihypertensive agents; 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (vastatins); phosphodiesterase-5 (PDE5) inhibitors; and to glucose lowering compounds. This invention also relates to pharmaceutical compositions and kits comprising such combinations and to methods of using such compositions and kits to treat or prevent the aforesaid diabetic complications. This invention also relates to novel compounds that are useful as intermediates for preparing the sulfonyl pyridazinone compounds of this invention.
The enzyme aldose reductase is involved in regulating the reduction of aldoses, such as glucose and galactose, to their corresponding polyols, such as sorbitol and galactitol. Sulfonyl pyridazinone compounds of Formula I of this invention, prodrugs of such compounds and pharmaceutically acceptable salts of such compounds and prodrugs, are useful as aldose reductase inhibitors in the treatment and prevention of diabetic complications of humans and other mammals associated with increased polyol levels in certain tissues (e.g., nerve, kidney, lens and retina tissue) of affected humans and other mammals.
French Patent Publication No. 2647676 discloses pyridazinone derivatives having substituted benzyl side chains and benzothiazole side chains described as being inhibitors of aldose reductase.
U.S. Pat. No. 4,251,528 discloses various aromatic carbocyclic oxophthalazinyl acetic acid compounds, which are described as possessing aldose reductase inhibitory properties.
Commonly assigned U.S. Pat. No. 4,939,140 discloses heterocyclic oxophthalazinyl acetic acid compounds useful as aldose reductast inhibitors.
Commonly assigned U.S. Pat. No. 4,996,204 discloses pyridopyridazinone acetic acid compounds useful as aldose reductase inhibitors.
The present invention is directed to compounds of Formula I, 
prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
A is S, SO or SO2;
R1 and R 2are each independently hydrogen or methyl;
R3 is Het1, xe2x80x94CHR 4Het1 or NR 6R7;
R4 is hydrogen or (C1-C3)alkyl;
R6 is (C1-C6)aikyl, aryl or Het2;
R7 is Het3;
Het1 is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyc, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyc, benzothiazolyl, indazolyg, benzisoxazolyl, benzisothiazolyi, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; Het1 is optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH) R2R13, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfenyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C6)alkyl optionally substituted with up to three fluoro, or (C1-C4)alkoxy optionally substituted with up to five fluoro; said benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, in the definition of substituents for Het1 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C6)alkylsulfenyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C1-C6)alkyl optionally substituted with up to five fluoro and (C1-C6)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of substituents for Het1 are optionally substituted with up to two substituents independently selected from hydroxy, halo, C1-C6)alkyl, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, C1-C4)alkyl-phenyl optionally substituted in the phenyl portion with one Cl, Br, OMe, Me or SO2-phenyl wherein said SO2-phenyl is optionally substituted in the phenyl portion with one Cl, Br, OMe, Me, (C1-C4)alkyl optionally substituted with up to five fluoro, or (C1-C4)alkoxy optionally substituted with up to three fluoro;
R12 and R13 are each independently hydrogen or (C1-C4)alkyl;
Het2 and Het3 are each independently imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy; Het2 and Het3 are each independently optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R18R19, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfenyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to three fluoro or (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, in the definition of substituents for Het2 and Het3 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of substituents for Het2 and Het3 are optionally substituted with up to two substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to three fluoro; and
R18 and R19 are each independently hydrogen or (C1-C4)alkyl, provided that when R3 is NR6R7, then A is SO2.
A preferred group of compounds, designated Group A, are those compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein A is SO2; R1 and R2 are each hydrogen; R3 is Het1 optionally substituted with up to a total of four substituents.
A preferred group of compounds within Group A, designated Group B, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Het1 is 5H-furo-[3,2cipyridin-4-one-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzothien-2-yl, imidazo[1,2a]pyridin-3-yl, pyrrol-1-yl, imidazol-1-yl, indazol-1-yl, tetrahydroquinol-1-yl or tetrahydroindol-1-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl or phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred group of compounds within Group B, designated Group C, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Het1 is indol-2-yl, benzofuran-2-yl, benzothiophen-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl or imidazo[1,2a]pyridin-4-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl and phenyl; said phenyl being optionally substituted with up to two substituents independently selected from fluoro, chloro and (C1-C6)alkyl.
A preferred group of compounds within Group C, designated Group D, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Het1 is indol-2-yl or indol-3-yl, said indol-2-yl or indol-3-yl being optionally independently substituted with up to two substituents each independently selected from fluoro, chloro and methyl.
A preferred compound within Group D is the compound wherein Het1 is 5-chloro-indol-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another preferred compound within Group D is the compound wherein Het1 is 5-fluoro-indol-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another preferred compound within Group D is the compound wherein Het1 is unsubstituted indol-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug.
Another preferred compound within Group D is the compound wherein wherein Het1 is unsubstituted indol-3-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another group of preferred compounds within Group C, designated Group E, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Het1 is benzofuran-2-yl optionally substituted with up to two substituents each independently selected from methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl, phenyl and hydroxy.
A group of preferred compounds within Group E are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Het1 is 5-chloro-benzofuran-2-yl, 5,7-dichloro-benzofuran-2-yl, benzofuran-2-yl, 5-chloro-3-methyl-benzofuran-2-yl, 5-fluoro-3-methyl-benzofuran-2-yl, 3-methyl-5-trifluoromethyl-benzofuran-2-yl, 5-chloro-3-phenyl-benzofuran-2-yl, 3-phenyl-benzofuran-2-yl, 3-(4-fluoro-phenyl)-benzofuran-2-yl, 5-chloro-benzofuran-2-yl and 3-ethyl-5-methyl-benzofuran-2-yl or 3-methyl-benzofuran-2-yl.
Another group of preferred compounds within Group E, designated Group F, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein Het1 is 3-methylbenzofuran-2-yl, optionally substituted with up to one additional substituent each independently selected from methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl, phenyl and hydroxy.
A preferred compound within Group F is the compound wherein said additional substituent is 5-chloro, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug. The potassium salt of this compound is particularly preferred.
Another preferred compound within Group F is the compound wherein said additional substituent is 5-fluoro, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another preferred compound within Group F is the compound wherein said additional substituent is 5-trifluoromethyl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another group of preferred compounds within Group C, designated Group G, are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein Het1 is benzothien-2-yl optionally substituted with up to two substituents each independently selected from methyl and chloro.
A preferred compound within Group G is the compound wherein Het1 is benzothien-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another preferred compound within Group G is the compound wherein Het1 is 5-chloro-3-methylbenzothien-2-yl, a prodrug thereof or a pharmaceutically acceptable salt of said compound or prodrug.
Another preferred group of compounds of Formula I are those compounds, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein A is SO2 and R3 is CHR4Het1, said Het1 being optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R12R13, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfenyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C6)alkyl optionally substituted with up to three fluoro, or (C1-C4)alkoxy optionally substituted with up to five fluoro; said benzyl, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, in the definition of substituents for Het1 are optionally substituted with up to three substituents independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C6)alkylsulfenyl, (C1-C6)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C6)alkyl optionally substituted with up to five fluoro and (C1-C6)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of substituents for Het1 are optionally substituted with up to two substituents independently selected from hydroxy, halo, C1-C6)alkyl, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, C1-C4)alkyl-phenyl optionally substituted in the phenyl portion with one Cl, Br, OMe, Me or SO2-phenyl wherein said SO2-phenyl is optionally substituted in the phenyl portion with one Cl, Br, OMe, Me, (C1-C4)alkyl optionally substituted with up to five fluoro, or (C1-C4)alkoxy optionally substituted with up to three fluoro;
R12 and R13 are each independently hydrogen or (C1-C4)alkyl.
This invention is also directed to compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
A is SO2;
R1 and R2 are each independently selected from hydrogen and methyl;
R3 is Het1;
Het1 is indol-2-yl, indol-3-yl, benzofuran-2-yl, benzofuran-3-yl, benzothien-2-yl, benzothien-3-yl, imidazo[1,2a]pyridinyl, pyrrolyl, imidazolyl, indazolyl, tetrahydroquinolyl or tetrahydroindolyl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from chloro, methyl, benzyl, methoxy, fluoro, 4-fluorophenyl, isopropyl, phenyl, trifluoromethyl, ethyl and hydroxy.
This invention is also directed to compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
A is SO2;
R1 and R2 are each independently selected from hydrogen and methyl;
R3 Het1;
Het1 is indol-2-yl or indol-3-yl, said indol-2-yl or indol-3-yl being optionally independently substituted with up to two substituents each independently selected from methyl, methoxy and chloro.
This invention is also directed to compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs, wherein:
A is SO2;
R1 and R2 are each independently selected from hydrogen and methyl;
R3 is Het1;
Het1 is benzofuran-2-yl, said benzofuran-2-yl being optionally independently substituted with up to two substituents each independently selected from methyl, methoxy, chloro, fluoro, ethyl, 4-fluorophenyl, trifluoromethyl, isopropyl, phenyl and hydroxy.
This invention is also directed to compounds selected from 6-(indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-methoxy-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3,5-dimethyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5,7-dichloro-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-isopropyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(6-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-hydroxy-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-hydroxy-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-methyl-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-phenyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-[4-fluorophenyl]-benzofuran-2-methylsulfonyl)-2H-pyridazin-3-one; 6-(thieno[2,3 b]pyridine-2-sulfonyl)-2H-pyridazin-3-one; 2-(6-oxo-1,6-dihydro-pyridazine-3-sulfonyl)-5H-furo[3.2-c]pyridin-4-one; 6-(5-chloro-3-ethyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(imidazo[1,2a]pyridine-3-sulfonyl)-2H-pyridazin-3-one; 6-(6-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-methoxy-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(6-fluoro-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(5,6-methylenedioxy-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(7-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-phenyl-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(N-benzylindole-5-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzofuran-2-methylsulfonyl)-2H-pyridazin-3-one; 6-(indole-3-sulfonyl)-2H-pyridazin-3-one; 6-(N-methylindole-2-sulfonyl)-2H-pyridazin-3-one; 6-(pyrrole-1-sulfonyl)2H-pyridazin-3-one; 6-(imidazole-1-sulfonyl)2H-pyridazin-3-one; 6-(indole-1-sulfonyl)2H-pyridazin-3-one; 6-(3-chloro-indole-1-sulfonyl)2H-pyridazin-3-one; 6-(3-chloro-indazole-1-sulfonyl)2H-pyridazin-3-one; 6-(3-methyl-indole-1-sulfonyl)-2H-pyridazin-3-one; 6-(tetrahydroquinoline-1-sulfonyl)-2H-pyridazin-3-one; 6-(3-[4-fluorophenyl]-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(imidazo[1,2a]pyridine-4-sulfonyl)-2H-pyridazin-3-one and 6-(2,3-tetrahydro-indole-1-sulfonyl)2H-pyridazin-3-one.
A preferred group of compounds of the preceding paragraph are 6-(indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5,7-dichloro-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-luoro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-hydroxy-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-[4-fluorophenyl]-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(thieno[2,3 b]pyridine-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-ethyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-phenyl-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzofuran-2-methylsulfonyl)-2H-pyridazin-3-one; 6-(indole-3-sulfonyl)-2H-pyridazin-3-one; 6-(furano[2,3b]pyridine-2-sulfonyl)-2H-pyridin-3-one; 6-(5-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; and 6-(imidazo[1,2a]pyridine-4-sulfonyl)-2H-pyridazin-3-one.
A preferred group of compounds of the preceding paragraph are 6-(benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5,7-dichloro-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one; 6-(3-[4-fluorophenyl]-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-ethyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-phenyl-2-sulfonyl)-2H-pyridazin-3-one; and 6-(5-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.
A preferred group of compounds of the preceding paragraph are 6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one; 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one and 6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one.
Another preferred group of compounds of Formula I includes 6-(indole-2-sulfonyl)-2H-pyridazin-3-one, 6-(5-chloro-indole-2-sulfonyl)-2H-pyridazin-3-one, 6-(indole-3-sulfonyl)-2H-pyridazin-3-one, 6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one, 6-(5-fluoro-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one, 6-(5-trifluoromethyl-3-methyl-benzofuran-2-sulfonyl)-2H-pyridazin-3-one, 6-(5-chloro-3-methyl-benzothiophene-2-sulfonyl)-2H-pyridazin-3-one and 6-(benzothiophene-3-sulfonyl)-2H-pyridazin-3-one.
This invention is also directed to pharmaceutical compositions comprising a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. It is preferred that said pharmaceutical compositions additionally comprise a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to methods for treating cardiac tissue ischemia in a mammal comprising administering to said mammal an effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt thereof. This invention is also directed to methods for treating cardiac tissue ischemia in a mammal comprising administering to said mammal a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable vehicle, carrier or diluent. In these methods, said mammal may be suffering from cardiac tissue ischemia or may be at risk of suffering from cardiac tissue ischemia. For example, a mammal at risk may be awaiting or undergoing cardiac, cardiovascular or other major surger.
This invention is also directed to methods of inhibiting aldose reductase in a mammal in need of inhibition of aldose reductase comprising administering an aldose reductase inhibiting amound of a compound of Formula I. This invention is also directed to methods of inhibiting aldose reductase in a mammal in need of inhibition of aldose reductase comprising administering a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable vehicle, carrier or diluent.
This invention is also directed to methods of treating one or more diabetic complications in a mammal suffering from one or more diabetic complications comprising administering to said mammal an effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Diabetic complications which may be treated by the methods of this invention include, but are not limited to, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, diabetic retinopathy, cataracts, foot ulcers, diabetic macroangiopathy and diabetic microangiopathy. This invention is also directed to methods of treating one or more diabetic complications in a mammal suffering from one or more diabetic complications comprising administering to said mammal an effective amount of a pharmaceutical composition as set forth herein.
This invention is also directed to pharmaceutical compositions comprising a combination of a first compound and a second compound; wherein said first compound is a compound of Formula I, a prodrug of said first compound or a pharmaceutically acceptable salt of said first compound or of said prodrug of said first compound and said second comopund is a NHE-1 inhibitor, an adenosine agonist, a sorbitol dehydrogenase inhibitor (SDI), a glycogen phosphorylase inhibitor (GPI), a selective serotonin reuptake inhibitor (SSRI), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (a vastatin), a thiazolidinedione antidiabetic agent (a glitazone), a xcex3-aminobutyric acid (GABA) agonist, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-II (A-II) receptor antagonist or a phosphodiesterase type 5 (PDE-5) inhibitor, a prodrug of said second compound or a pharmaceutically acceptable salt of said second compound or of said prodrug of said second compound. Particularly preferred second compounds for use in this invention include, but are not limited to, atorvastatin, sildenafil, sertraline, pregabalin, gabapentin, fluoxetine, cerivastatin, pravastatin, mevastatin, lovastatin, simvastatin, pioglitazone, rosiglitazone, benazepril and captopril, and pharmaceutically acceptable salts of said second compounds. This invention is also directed to methods of treating one or more diabetic complications in a mammal comprising administering to a mammal in need of such treatment a pharmaceutical composition as set forth in this paragraph.
This invention is also directed to a method of treating one or more diabetic complications in a mammal comprising administering to a mammal in need of such treatment a combination of a first compound and-a second compound; wherein said first compound is a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug, and said second comopund is a NHE-1 inhibitor, an adenosine agonist, a sorbitol dehydrogenase inhibitor (SDI), a glycogen phosphorylase inhibitor (GPI), a selective serotonin reuptake inhibitor (SSRI), a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (a vastatin), a thiazolidinedione antidiabetic agent (a glitazone), a xcex3-aminobutyric acid (GABA) agonist, an angiotensin converting enzyme (ACE) inhibitor, an angiotensin-II (A-II) receptor antagonist or a phosphodiesterase type 5 (PDE-5) inhibitor, a prodrug of said second compound or a pharmaceutically acceptable salt of said second compound or of said prodrug.
This invention is also directed to kits comprising:
a) a first unit dosage form comprising a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound of Formula I or said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent;
b) a second unit dosage form comprising:
a NHE-1 inhibitor;
an adenosine agonist;
a sorbitol dehydrogenase inhibitor;
a selective serotonin reuptake inhibitor;
a vastatin;
an angiotensin converting enzyme inhibitor;
a thiazolidinedione antidiabetic agent;
a glycogen phosphorylase inhibitor;
an angiotensin II receptor antagonist;
a xcex3-aminobutyric acid (GABA) agonist; and
a phosphodiesterase type 5 inhibitor;
a prodrug of said sorbitol dehydrogenase inhibitor, selective serotonin reuptake inhibitor, vastatin, angiotensin converting enzyme inhibitor, thiazolidinedione antidiabetic agent, glycogen phosphorylase inhibitor, angiotensin II reuptake inhibitor, xcex3-aminobutyric acid agonist or phosphodiesterase type 5 inhibitor, or a pharmaceutically acceptable salt thereof or of said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent; and
c) a container.
This invention is also directed to intermediate compounds of Formula II, 
wherein:
A is S, SO or SO2;
Z is (C1-C6)alkyl, phenyl or benzyl, said benzyl or phenyl being optionally substituted with one or two substituents each independently selected from chloro and methyl;
R1 and R2 are each independently hydrogen or methyl;
R3a is Het1, xe2x80x94CHR4Het1;
R4 is hydrogen or (C1-C3)alkyl;
Het1 is pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolyl, quinoxalyl, phthalazinyl, cinnolinyl, naphthyridinyl, pteridinyl, pyrazinopyrazinyl, pyrazinopyridazinyl, pyrimidopyridazinyl, pyrimidopyrimidyl, pyridopyrimidyl, pyridopyrazinyl, pyridopyridazinyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazolopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, pyrrolopyrimidyl, furopyrimidyl, thienopyrimidyl, imidazolopyrimidyl, oxazolopyrimidyl, thiazolopyrimidyl, pyrazolopyrimidyl, isoxazolopyrimidyl, isothiazolopyrimidyl, pyrrolopyrazinyl, furopyrazinyl, thienopyrazinyl, imidazolopyrazinyl, oxazolopyrazinyl, thiazolopyrazinyl, pyrazolopyrazinyl, isoxazolopyrazinyl, isothiazolopyrazinyl, pyrrolopyridazinyl, furopyridazinyl, thienopyridazinyl, imidazolopyridazinyl, oxazolopyridazinyl, thiazolopyridazinyl, pyrazolopyridazinyl, isoxazolopyridazinyl or isothiazolopyridazinyl; Het1 is independently optionally substituted with up to a total of four substituents each independently selected from halo, formyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylenyloxycarbonyl, (C1-C4)alkoxy-(C1-C4)alkyl, C(OH)R12R13, (C1-C4)alkylcarbonylamido, (C3-C7)cycloalkylcarbonylamido, phenylcarbonylamido, phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, (C1-C4)alkylsulfenyl, (C1-C4)alkylsulfonyl, (C3-C7)cycloalkyl, (C1-C4)alkyl optionally substituted with up to three fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said phenyl, naphthyl, imidazolyl, pyridyl, triazolyl, benzimidazolyl, oxazolyl, isoxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothiazolyl, pyrrolyl, pyrazolyl, quinolyl, isoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy, pyridylsulfonyl, furanyl, phenoxy, thiophenoxy, in the definition of the substituents of Het1 are optionally substituted with up to three substituents each independently selected from hydroxy, halo, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl optionally substituted with up to five fluoro and (C1-C4)alkoxy optionally substituted with up to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl and pyrazolyl in the definition of the substituents of Het1 are optionally substituted with up to two substituents each independently selected from hydroxy, halo, C1-C4)alkyl, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl and C1-C4)alkyl-phenyl optionally substituted in the phenyl portion with one Cl, Br, OMe, Me or SO2-phenyl wherein said SO2-phenyl is optionally substituted in the phenyl portion with one Cl, Br, OMe, Me, (C1-C4)alkyl optionally substituted with up to five fluoro, or (C1-C4)alkoxy optionally substituted with up to three fluoro; R12 and R13 are each independently hydrogen or (C1-C4)alkyl.
A preferred group of compounds of Formula II, designated Group AA, are those compounds and pharmaceutically acceptable salts thereof wherein A is S, R1 and R2 are each H, R3a is Het1 and Z is methyl.
A preferred group of compounds of Group AA, designated Group BB, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is 5H-furo-[3,2c]pyridin-4-one-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzothien-2-yl, imidazo[1,2a]pyridin-3-yl, pyrrol-1-yl, imidazol-1-yl, indazol-1-yl, tetrahydroquinol-1-yl or tetrahydroindol-1-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred group of compounds of Group BB, designated Group CC, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred compound of Group CC is the compound wherein Het1 is 5-chloro-3-methyl-benzofuran-2-yl and pharmaceutically acceptable salts thereof.
Another preferred group of compounds of Formula II, designated Group DD, are those compounds and pharmaceutically acceptable salts thereof wherein A is SO2, R1 and R2 are each H, R3a is Het1 and Z is methyl.
A preferred group of compounds of Group DD, designated Group EE, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is 5H-furo-[3,2c]pyridin-4-one-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzothien-2-yl, imidazo[1,2a]pyridin-3-yl, pyrrol-1-yl, imidazol-1-yl, indazol-1-yl, tetrahydroquinol-1-yl or tetrahydroindol-1-yl, wherein said Het1 is optionally-independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred group of compounds of Group EE, designated Group FF, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred compound of Group FF is the compound wherein Het1 is 5-chloro-3-methyl-benzofuran-2-yl and pharmaceutically acceptable salts thereof.
Another preferred group of compounds of Formula II, designated Group GG, are those compounds and pharmaceutically acceptable salts thereof wherein A is SO, R1 and R2 are each H, R3a is Het1 and Z is methyl.
A preferred group of compounds within Group GG, designated Group HH, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is 5H-furo-[3,2c]pyridin-4-one-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzothien-2-yl, imidazo[1,2a]pyridin-3-yl, pyrrol-1-yl, imidazol-1-yl, indazol-1-yl, tetrahydroquinol-1-yl or tetrahydroindol-1-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred group of compounds within Group HH, designated Group II, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred compound within Group II is the compound wherein Het1 is 5-chloro-3-methyl-benzofuran-2-yl and pharmaceutically acceptable salts thereof.
Another preferred group of compounds of Formula I, designated Group JJ, are those compounds and pharmaceutically acceptable salts thereof wherein A is S or SO; R1 and R2 are each H; and R3 is Het1.
A preferred group of compounds of Group JJ, designated Group KK, are those compounds and pharmaceutically acceptable salts thereof wherein A is S and Het1 is 5H-furo-[3,2c]pyridin-4-one-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzothien-2-yl, imidazo[1,2a]pyridin-3-yl, pyrrol-1-yl, imidazol-1-yl, indazol-1-yl, tetrahydroquinol-1-yl or tetrahydroindol-1-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl or phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred group of compounds of Group KK, designated Group LL, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred compound of Group LL is the compound wherein Het1 is 5-chloro-3-methyl-benzofuran-2-yl and pharmaceutically acceptable salts thereof.
Another group of preferred compounds within Group JJ, designated Group MM, are those compounds and pharmaceutically acceptable salts thereof wherein A is SO and Het1 is 5H-furo-[3,2c]pyridin-4-one-2-yl, furano[2,3b]pyridin-2-yl, thieno[2,3b]pyridin-2-yl, indol-2-yl, indol-3-yl, benzofuran-2-yl, benzothien-2-yl, imidazo[1,2a]pyridin-3-yl, pyrrol-1-yl, imidazol-1-yl, indazol-1-yl, tetrahydroquinol-1-yl or tetrahydroindol-1-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A group of preferred compounds within Group MM, designated Group NN, are those compounds and pharmaceutically acceptable salts thereof wherein Het1 is indol-2-yl, benzofuran-2-yl or benzothien-2-yl, wherein said Het1 is optionally independently substituted with up to a total of two substituents each independently selected from fluoro, chloro, bromo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, hydroxy, benzyl and phenyl; said benzyl and phenyl are each optionally independently substituted with up to three halo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkylsulfonyl, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfenyl, trifluoromethyl or hydroxy.
A preferred compound within Group NN is the compound wherein Het1 is 5-chloro-3-methyl-benzofuran-2-yl and pharmaceutically acceptable salts thereof.
Particularly preferred intermediates for use in the synthesis of certain of the compounds of Formula I of this invention include, but are not limited to 6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-2H-pyridazin-3-one; 3-methoxy-6-(5-chloro-3-methyl-benzofuran-2-sulfonyl)-pyridazine; 3-methoxy-6-(5-chloro-3-methyl-benzofuran-2-sulfenyl)-pyridazine; 3-methoxy-6-(5-chloro-3-methyl-benzofuran-2-sulfinyl)-pyridazine; and 6-(5-chloro-3-methyl-benzofuran-2-sulfinyl)-2H-pyridazin-3-one.
Another preferred intermediate is 5-chloro-2-mercapto-3-methylbenzofuran.
The subject invention also includes isotopically-labeled compounds, which are identical to those recited in Formula I and Formula II, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31p, 32p, 35S, 18F and 36Cl, respectively. Compounds of Formula I and Formula II of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of Formula I and Formula II of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The term xe2x80x9creductionxe2x80x9d is intended to include partial prevention or prevention which, although greater than that which would result from taking no compound or from taking a placebo, is less than 100% in addition to substantially total prevention.
The term xe2x80x9ctreatingxe2x80x9d, xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes preventative (e.g., prophylactic) and palliative treatment.
By xe2x80x9cpharmaceutically acceptablexe2x80x9d it is meant the carrier, diluent, excipients, and/or salt must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
The expression xe2x80x9cprodrugxe2x80x9d refers to a compound that is a drug precursor which, following administration, releases the drug in vivo via some chemical or physiological process (e.g., a prodrug on being brought to the physiological pH or through enzyme action is converted to the desired drug form).
By xe2x80x9calkylenexe2x80x9d is meant saturated hydrocarbon (straight or branched chain) wherein a hydrogen atom is removed from each of the terminal carbons. Exemplary of such groups (assuming the designated length encompasses the particular example) are methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene.
By xe2x80x9csulfenylxe2x80x9d is meant S, by xe2x80x9csulfinylxe2x80x9d is meant SO and by xe2x80x9csulfonylxe2x80x9d is meant SO2.
By xe2x80x9chaloxe2x80x9d is meant chloro, bromo, iodo, or fluoro.
By xe2x80x9calkylxe2x80x9d is meant straight or branched chain saturated hydrocarbon or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, neopentyl, tertiary pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, hexyl, isohexyl, heptyl and octyl.
By xe2x80x9calkoxyxe2x80x9d is meant straight chain saturated alkyl or branched saturated alkyl bonded through an oxygen. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy and octoxy.
By xe2x80x9carylxe2x80x9d is meant a carbon-containing aromatic ring. Examples of such aryl groups include phenyl and naphthyl.
It is to be understood that if a carbocyclic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing ring atoms without denoting a specific point of attachment, then all possible points are intended, whether through a carbon atom or, for example, a trivalent nitrogen atom. For example, the term xe2x80x9cpyridylxe2x80x9d means 2-, 3-, or 4-pyridyl, the term xe2x80x9cthienylxe2x80x9d means 2-, or 3-thienyl, and so forth.
The expression xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable cationic salts, where appropriate. The expression xe2x80x9cpharmaceutically-acceptable cationic saltsxe2x80x9d is intended to include, but is not limited to, such salts as the alkali metal salts, (e.g., sodium and potassium), alkaline earth metal salts (e.g., calcium and magnesium), aluminum salts, ammonium salts, and salts with organic amines such as benzathine (N,Nxe2x80x2-dibenzylethylenediamine), choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), benethamine (N-benzylphenethylamine), diethylamine, piperazine, tromethamine (2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The expression xe2x80x9cpharmaceutically-acceptable acid addition saltsxe2x80x9d is intended to include, but is not limited to, such salts as the hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogenphosphate, acetate, succinate, citrate, methanesulfonate (mesylate) and p-toluenesulfonate (tosylate) salts. A particularly preferred salt is the sodium salt.
Pharmaceutically acceptable cationic salts of the compounds of this invention may be readily prepared by reacting the free acid form of said compounds with an appropriate base, usually one equivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, potassium carbonate, sodium carbonate, magnesium hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, piperazine and tromethamine. The salt is isolated by concentration to dryness or by addition of a non-solvent. In many cases, salts are preferably prepared by mixing a solution of the acid with a solution of a different salt of the cation (sodium or potassium ethylhexanoate, magnesium oleate), and employing a solvent (e.g., ethyl acetate) from which the desired cationic salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent. They can be further purified by crystallization from (C1-C6)alcoholic solvents such as methanol, ethanol or isopropanol or from ketonic solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
The acid addition salts of the compounds of this invention may be readily prepared by reacting the free base form of said compounds with the appropriate acid. When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is employed. However when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent. They can be further purified by crystallization from (C1-C6)alcoholic solvents such as methanol, ethanol or isopropanol or from ketonic solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone.
Prodrugs of this invention may be formed by substituting a compound of Formula I at the 2-nitrogen position of the pyridazin-3-one ring as shown below: 
wherein Pr is (C1-C6)alkyl or benzyl. These prodrugs may be prepared by reacting a compound of Formula I with a compound of the formula Prxe2x80x94X, wherein Pr is as defined above and X is bromo, chloro or iodo in the presence of a base such as, for example, sodium hydride or n-butyl lithium in a reaction inert solvent, such as, for example, dimethylformamide, tetrahydrofuran or ether. The reaction is generally carried out at temperatures ranging from about 0xc2x0 C. to about room temperature when using sodium hydride as the base. When using n-butyl lithium or a similar base, the reaction is generally carried out at temperatures ranging from about xe2x88x9260xc2x0 C. to about 0xc2x0 C. Other processes for preparing such prodrugs will be readily apparent to the skilled person.
As used herein, the expressions xe2x80x9creaction inert solventxe2x80x9d and xe2x80x9cinert solventxe2x80x9d refer to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
The chemist of ordinary skill will recognize that certain compounds of Formula I of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Compounds of Formula I may be chiral. In such cases, the isomer wherein R1 has the R configuration is preferred. Hydrates and solvates of the compounds of Formula I of this invention are also included.
The chemist of ordinary skill in the art will also recognize that certain compounds of Formula I of this invention can exist in tautomeric form, i.e., that an equilibrium exists between two isomers which are in rapid equilibrium with each other. A common example of tautomerism is keto-enol tautomerism, i.e., 
Examples of compounds which can exist as tautomers include hydroxypyridines, hydroxypyrmidines and hydroxyquinolines. In particular, a person skilled in the art will recognize that the pyridazinones of the instant invention can exist as two separate tautomers, e.g., 
Other examples will be recognized by those skilled in the art. All such tautomers and mixtures thereof are included in this invention.
DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide. THF means tetrahydrofuran.
Whenever the structure of a cyclic radical is shown with a bond drawn from outside the ring to inside the ring, it will be understood by those of ordinary skill in the art to mean that the bond may be attached to any atom on the ring with an available site for bonding. If the cyclic radical is a bicyclic or tricyclic radical, then the bond may be attached to any atom on any of the rings with an available site for bonding. For example, 
represents any or all of the following radicals: 
Other features and advantages will be apparent from the specification and claims which describe the invention.
In general the compounds of Formula I of this invention can be made by processes which include processes analogous to those known in the chemical arts, particularly in light of the description contained herein. Certain processes for the manufacture of the compounds of Formula I of this invention are provided as further features of the invention and are illustrated by the following reaction schemes. Other processes are described in the experimental section. 
According to Scheme 1, compounds of Formula I, wherein R1 and R2 are as defined above and R3 is Het1, can be prepared from the corresponding pyridazine of formula 1-2 and a heterocyclic thiol of formula 1-1. A thiol 1-1, in which R3 of the compounds of Formula I is Het1, is reacted with a base such as an alkali metal (C1-C6)alkoxide in a (C1-C6) alkanol, to obtain the alkali metal salt of said thiol. Preferred alkali metal (C1-C6)alkoxides include, but are not limited to, sodium methoxide, sodium ethoxide and potassium t-butoxide. After evaporating the excess solvent, the resulting alkali metal salt of said thiol is refluxed with a compound of formula 1-2 wherein Z1 and Z2 are each independently selected from chloro, (C1-C6)alkoxy, phenyloxy or benzyloxy, said benzyloxy or phenyloxy being optionally substituted with one or two chloro or methyl groups in an aromatic hydrocarbon solvent or solvent system, for example, toluene, benzene or xylene. The reaction is allowed to stir overnight to obtain a compound of formula 1-3. The reaction is usually conducted at ambient pressure and at the refluxing temperature of the solvent used. Compounds of formula 1-3 can also be prepared by reacting compounds 1-2, wherein R1, R2, Z1 and Z2 are as defined above with a compound of formula 1-1 in a reaction inert solvent such as a polar non-aqueous solvent containing an alkali or alkali earth metal hydride or an alkali or alkali earth (C1-C4)alkoxide. Preferred such solvents include, but are not limited to, acetonitrile and ether solvents such as diglyme, tetrahydrofuran (THF) and dimethylformamide (DMF). Preferred such alkali or alkali earth metal hydrides include, but are not limited to, sodium hydride. Preferred alkali or alkali earth metal (C1-C4)alkoxides include, but are not limited to, potassium t-butoxide. The preferred metal hydride is sodium hydride. A particularly preferred solvent is DMF. Compounds of formula 1-3 can also be prepared by reacting a compound of formula 1-1 with a compound of formula 1-2, wherein the variables are as defined above, in a reaction inert solvent such as DMF, THF, diglyme or dioxane containing sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate. This reaction is usually conducted at ambient pressure and at temperatures between about 60xc2x0 C. and about 120xc2x0 C. A compound of formula 1-3 can be oxidized to afford a sulfoxide or a sulfonyl compound of formula 1-4a and/or 1-4b, respectively. A preferred procedure is oxidation of a compound of formula 1-3 with 30% hydrogen peroxide in the presence or absence of an organic acid such as formic acid or acetic acid. Another preferred oxidation procedure involves the use of peracid in the corresponding organic acid as solvent. Yet another preferred procedure is oxidation of a compound of formula 1-3 with a peracid, for example meta-chloroperbenzoic acid (MCPBA), in a halocarbon solvent, for example, methylene chloride, chloroform or ethylene chloride. In any case, the reaction is conducted at ambient pressure and at temperatures between about 20xc2x0 C. and about xe2x88x9240xc2x0 C. with careful reaction monitoring to avoid formation of N-oxides by over-oxidation at the nitrogen atom. The oxidation reaction is usually complete within three to six hours and proceeds through sulfoxide 1-4a, but occasionally may be complete prior to the passage of three hours, as determined by a person skilled in the art. If the reaction is conducted at between about 20xc2x0 C. and about 30xc2x0 C., and is stopped at between one to three hours, sulfoxide 1-4a can be isolated using separation procedures well known to a person skilled in the art. The resulting sulfone of formula 1-4b can then be hydrolyzed with a mineral acid such as, but not limited to, concentrated hydrochloric acid with no solvent or in a reaction inert solvent such as an ether solvent, for example, dioxane, tetrahydrofuran or diethyl ether, to obtain a compound of Formula 1. The hydrolysis reaction is generally conducted at ambient pressure and at the refluxing temperature of the solvent used. 
According to Scheme 1A, compounds of Formula I can also be prepared by reversing the order of the last two steps of Scheme 1, i.e., by formation of the oxo compound of Formula I prior to oxidation of the sulfide of formula 1-5 to the sulfone of Formula I via the sulfoxide of Formula 1-6. Thus, a compound of formula 1-3 is hydrolyzed in the manner described above to afford a pyridazinone compound of formula 1-5, which is then oxidized in the manner described above to afford a compound of Formula 1. Compounds of formula 1-6 can also be prepared by hydrolyzing compounds of formula 1-4a as described for Scheme 1.
According to Scheme 2, compounds of Formula I can be prepared by reacting compounds of the formula Het1-Z3 where Z3 is bromide, iodide or an acidic hydrogen with a suitable organometallic base to form compounds of the formula Het1-Z4 wherein Z4 is the cation corresponding to the organometallic base. Het1xe2x80x94Z4 may in turn may be reacted with a fluorosulfonyl pyridazine compound of the formula 2-3 to form a sulfonyl pyridazine of the formula 2-4 which may be hydrolyzed to form a compound of Formula I. In the case where Z3 is an acidic hydrogen, the hydrogen will be acidic enough such that said hydrogen is removable by reaction with a base such as, but not limited to, (C1-C6)alkyllithium, lithium diisopropylamide (LDA) or phenyl lithium. Thus, a compound of formula 2-1 in which Z3 is bromide, iodide or a hydrogen of sufficient acidity, is reacted with a base such as, but not limited to, (C1-C6)alkyllithium, lithium diisopropylamide (LDA) or phenyl lithium to prepare a compound of formula 2-2, wherein Z4 is lithium. A hydrogen of sufficient acidity is a hydrogen that can be removed from Het1xe2x80x94Z3 by the bases mentioned in the preceding sentence. The reaction is conducted in a reaction inert solvent such as an ether or a hydrocarbon solvent or a mixture of such solvents. Preferred solvents include, but are not limited to, diethyl ether, tetrahydrofuran, diglyme, benzene and toluene or mixtures thereof. The reaction is conducted at temperatures from about xe2x88x9278xc2x0 C. to about 0xc2x0 C. and at ambient pressure. A compound of formula 2-2 is reacted with a compound of formula 2-3 wherein Z2 is chloro, (C1-C6)alkoxy, phenyloxy or benzyloxy, said phenyloxy or benzyloxy being optionally substituted with one or two chloro or methyl groups to form compounds of formula 2-4 wherein Z2 is as defined above. The reaction is conducted in a reaction inert solvent such as an ether or a hydrocarbon solvent or a mixture of such solvents. Preferred solvents include, but are not limited to, diethyl ether, tetrahydrofuran, diglyme, benzene and toluene or mixtures thereof. The reaction is conducted at temperatures ranging from about xe2x88x9278xc2x0 C. to about 0xc2x0 C. and at ambient pressure. Compounds 2-4 are hydrolyzed to form compounds of Formula I as described above.
Also according to Scheme 2, compounds of formula 2-4 may be prepared by reacting a compound of formula 2-2 wherein Z4 is MgBr or Mgl using standard Grignard reaction conditions, e.g., by reacting a compound of formula 2-1 wherein Z3 is bromide or iodide with magnesium to form the compound of formula 2-2 which is reacted, preferably in situ, with a compound of formula 2-3 wherein Z2 is as defined above. The reaction is generally conducted in a reaction inert solvent such as an ether or a hydrocarbon solvent or a mixture of such solvents. Preferred solvents include, but are not limited to, diethyl ether, tetrahydrofuran, diglyme, benzene and toluene or mixtures thereof. The reaction temperature ranges from about xe2x88x9210xc2x0 C. to about 40xc2x0 C. Formation of the Grignard reagent of formula 2-2 may be readily accomplished according to methods well known to those skilled in the art. 
According to Scheme 3, compounds of Formula I wherein R1, R2, Z2 and Het1 are defined as described above and R3 is CHR4xe2x80x94Het1 may be prepared by reacting a compound of the formula 3-1 with a compound of the formula 3-2 followed by further modification. Thus, a compound of the formula 3-1 wherein L is a leaving group such as chloro, bromo, iodo, methanesulfonyloxy, phenylsulfonyloxy wherein said phenyl of said phenylsulfonyloxy may be optionally substituted by one nitro, chloro, bromo or methyl is reacted with a compound of the formula 3-2, wherein Z2 is as described above, to form a compound of the formula 3-3. The reaction is conducted in a reaction inert solvent such as methylene chloride, chloroform, diethyl ether, tetrahydrofuran, dioxane, acetonitrile or dimethylformamide at a temperature ranging from about room temperature to about 90xc2x0 C. The reaction is conducted at ambient pressure. A compound of the formula 3-3 is then oxidized to form a sulfoxide or sulfonyl compound of the formula 3-4a and/or 3-4b, respectively, by reacting said compound of formula 3-3 with an oxidizing agent such as metachloroperbenzoic acid (MCPBA) in a reaction inert solvent or hydrogen peroxide in acetic acid. The sulfoxide of formula 3-4a may be isolated by halting the oxidation reaction as described in Scheme 1 above. When MCPBA is used, preferred reaction inert solvents include such solvents as methylene chloride and chloroform. The reaction is ordinarily performed at room temperature. When hydrogen peroxide is used as the oxidizing agent, the reaction is carried out as described above. Compounds of formula 3-4b thus prepared may be hydrolyzed to form compounds of Formula I according to conditions described in Scheme 1 above. 
According to Scheme 4, compounds of Formula I wherein R1, R2 and Z are defined as set forth above and R3 is xe2x80x94NR6R7 may be prepared from compounds of formula 2-3. Thus, a compound of formula 2-3 is reacted with an amine of the formula HNR6R7, wherein R6 and R7 are defined as set forth above, in the presence of excess HNR6R7 or a tertiary amine such as, but not limited to, triethyl amine or diisopropyl ethyl amine in a reaction inert solvent to form a compound of the formula 3-1. Preferred reaction inert solvents for this reaction include, but are not limited to, methylene chloride, chloroform, diethyl ether, tetrahydrofuran and dioxane. The reaction is preferably conducted at a temperature ranging from about 0xc2x0 C. to about 100xc2x0 C. Compounds of formula 3-1 thus prepared may be hydrolyzed to form compounds of Formula I as described above.
The starting materials and reagents for the above described compounds are also readily available or can be easily synthesized by those skilled in the art using conventional methods of organic synthesis. For example, many of the compounds used herein are related to, or are derived from, compounds found in nature, in which there is a large scientific interest and commercial need, and accordingly many such compounds are commercially available or are reported in the literature or are easily prepared from other commonly available substances by methods which are reported in the literature.
The compounds of Formula I of the present invention inhibit the bioconversion of glucose to sorbitol catalyzed by the enzyme aldose reductase and as such have utility in the treatment of diabetic complications including but not limited to such complications as diabetic neuropathy, diabetic retinopathy, diabetic nephropathy, diabetic cardiormyopathy, diabetic cataracts, tissue ischemia, diabetic microangiopathy and diabetic macroangiopathy. Such aldose reductase inhibition is readily determined by those skilled in the art according to standard assays known to those skilled in the art (e.g., B. L. Mylari at al., J. Med. Chem., 1991, 34, 108-122) and according to the protocol described in Example 51.
Cardioprotection, as indicated by a reduction in infarcted myocardium, can be induced pharmacologically using adenosine receptor agonists in isolated, retrogradely perfused rabbit hearts as an in vitro model of myocardial ischemic preconditioning (Liu et al., Cardiovasc. Res., 28:1057-1061, 1994). The in vitro test described following demonstrates that a test compound (i.e., a compound as claimed herein) can also pharmacologically induce cardioprotection, i.e., reduced myocardial infarct size, when administered to a rabbit isolated heart. The effects of the test compound are compared to ischemic preconditioning and the Al1/A3 adenosine agonist, APNEA 2-(4-aminophenyl)ethyl adenosine), that has been shown to pharmacologically induce cardioprotection in the rabbit isolated heart (Liu et al., Cardiovasc. Res., 28:1057-1061, 1994). The exact methodology is described below.
The protocol used for these experiments closely follows that described by Liu et al., Cardiovasc. Res., 28:1057-1061, 1994. Male New Zealand White rabbits (3-4 kg) are anesthetized with sodium pentobarbital (30 mg/kg, i.v.). After deep anesthesia is achieved (determined by the absence of an ocular blink reflex) the animal is intubated and ventilated with 100% O2 using a positive pressure ventilator. A left thoracotomy is performed, the heart exposed, and a snare (2-0 silk) is placed loosely around a branch of the left anterior descending coronary artery, approximately ⅔ of the distance towards the apex of the heart. The heart is removed from the chest and rapidly ( less than 30 cc) mounted on a Langendorff apparatus. The heart is retrogradely used via the aorta in a non-recirculating manner with a modified Krebs solution (NaCI 118.5 mM, KCI 4.7 mM, MgSO4 1.2 mM, KH2PO.sub.41.2 mM, NaHCO3 24.8 mM, CaCI2 2.5 mM, and glucose 10 mM), at a constant pressure of 80 mmHg and a temperature of 37xc2x0 C. Perfusate pH is maintained at 7.4-7.5 by bubbling with 95% O2/5% CO2. Heart temperature is tightly controlled by using heated reservoirs for the physiological solution and water jacketing around both the perfusion tubing and the isolated heart. Heart rate and left ventricular pressures are determined via a latex balloon which is inserted in the left ventricle and connected by stainless steel tubing to a pressure transducer. The intraventricular balloon is inflated to provide a systolic pressure of 80-100 mmHg, and a diastolic pressure xe2x89xa610 mmHg. Total coronary flow is also continuously monitored using an in-line flow probe and normalized for heart weight.
The heart is allowed to equilibrate for 30 min, over which time the heart must show stable left ventricular pressures within the parameters outlined above. If the heart rate falls below 180 bpm at any time prior to the 30 min period of regional ischemia, the heart is paced at about 200 bpm for the remainder of the experiment. Ischemic preconditioning is induced by total cessation of cardiac perfusion (global ischemia) for 5 min, followed by reperfusion for 10 min. The global ischemia/reperfusion is repeated one additional time, followed by a 30 min regional ischemia. The regional ischemia is provided by tightening the snare around the coronary artery branch. Following the 30 min regional ischemia, the snare is released and the heart reperfused for an additional 120 min.
Pharmacological cardioprotection is induced by infusing the test compound at predetermined concentrations, starting 30 min prior to the 30 min regional ischemia, and continuing until the end of the 120 min reperfusion period. Hearts, which receive test compounds, do not undergo the two periods of ischemic preconditioning. The reference compound, APNEA (500 nM) is perfused through hearts (which do not receive the test compound) for a 5 min period which ends 10 min before the 30 min regional ischemia.
At the end of the 120 min reperfusion period, the coronary artery snare is tightened, and a 0.5% suspension of fluorescent zinc cadmium sulfate particles (1-10 xcexcM) is perfused through the heart; this stains all of the myocardium, except that area at risk for infarct development (area-at-risk). The heart is removed from the Langendorff apparatus, blotted dry, weighed, wrapped in aluminum foil and stored overnight at xe2x88x9220xc2x0 C. The next day, the heart is sliced into 2 mm transverse sections from the apex to just above the coronary artery snare. The slices are stained with 1% triphenyl tetrazolium chloride (TTC) in phosphate-buffered saline for 20 min at 37xc2x0 C. Since TTC reacts with living tissue (containing AND-dependent dehydrogenases), this stain differentiates between living (red stained) tissue, and dead tissue (unstained infarcted tissue). The infarcted area (no stain) and the area-at-risk (no fluorescent particles) are calculated for each slice of left ventricle using a precalibrated image analyzer. To normalize the ischemic injury for difference in the area-at-risk between hearts, the data is expressed as the ratio of infarct area vs. area-at-risk (% IA/MR).
The activity and thus utility of the compounds of the present invention as medical agents in providing protection from ischemic damage to tissue in a mammal can be further demonstrated by the activity of the compounds in the in vitro assay described herein below. The assay also provides a means whereby the activities of the compounds of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for inducing protection from ischemia.
The activity of an aldose reductase inhibitor in a tissue can be determined by testing the amount of aldose reductase inhibitor that is required to inhibit tissue sorbitol or lower tissue fructose (by inhibiting its production from sorbitol consequent to blocking aldose reductase). While not wishing to be bound by any particular theory or mechanism, it is believed that an aldose reductase inhibitor, by inhibiting aldose reductase, prevents or reduces ischemic damage as described hereinafter in the following paragraph and scheme.
When the supply of oxygenated blood to a tissue is interrupted or slowed down (ischemia) the cells in the oxygen-deficient tissue derive their energy (ATP) from glucose via glycolysis (which does not require the presence of oxygen). Glycolysis also requires a supply of NAD+ and in an ischemic tissue the length of time glycolysis can be maintained becomes sensitive to the supply of NAD+. Thus, it follows that sparing NAD+. use by ARIs will enhance or prolong the ability of ischemic tissue to carry out glycolysis, i.e., to produce energy in the absence of oxygen and in turn enhance and prolong the survival of the cells in the tissue. Since, inhibition of AR will retard depletion of the tissue""s NAD+, an aldose reductase inhibitor is an effective anti-ischemic agent.
This invention also relates to therapeutic methods of treating or preventing diabetic complications in which a compound of Formula I of this invention is administered as part of an appropriate dosage regimen designed to obtain the benefits of the therapy. The appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the compound will depend upon the compound of Formula I of this invention being used, the type of pharmaceutical formulation being used, the characteristics of the subject being treated and the severity of the conditions. Generally, in carrying out the methods of this invention, an effective dosage for the compounds of Formula I of this invention is in the range of about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses. A preferred dosage range for the compounds of Formula I of this invention is about 0.1 mg/kg/day to about 100 mg/kg/day in single or divided doses. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
The standard assays used to determine aldose reductase inhibiting activity, as referenced above, may be used to determine dosage levels in humans and other mammals of the compounds of Formula I of this invention. Such assays provide a means to compare the activities of the compounds of Formula I of this invention and other known compounds that are aldose reductase inhibitors. The results of these comparisons are useful for determining such dosage levels.
The term xe2x80x9cSecond Agentsxe2x80x9d hereinafter refers collectively to pharmaceutical compounds or agents that are NHE-1 inhibitors, adenosine agonists, sorbitol dehydrogenase inhibitors, selective serotonin reuptake inhibitors, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, angiotensin converting enzyme inhibitors, thiazolidinedione antidiabetic agents, glycogen phosphorylase inhibitors, angiotensin II receptor antagonists, y-aminobutyric acid agonist, phosphodiesterase type 5 inhibitors, prodrugs of said compounds or agents, and pharmaceutically acceptable salts of such compounds, agents and prodrugs. Use of the term in singular form, as in xe2x80x9ca Second Agentxe2x80x9d hereinafter refers to a pharmaceutical agent selected from said Second Agents. A Second Agent may be a pharmaceutical agent that shares more than one of the foregoing characteristics.
An additional aspect of this invention relates to pharmaceutical compositions comprising a compound of Formula I of this invention, and a Second Agent. Such compositions are hereinafter referred to collectively as the xe2x80x9ccombination compositionsxe2x80x9d.
This invention also relates to therapeutic methods for treating or preventing diabetic complications in a mammal wherein a compound of Formula I of this invention and a Second Agent are administered together as part of the same pharmaceutical composition or separately. Such methods are hereinafter referred to collectively as the xe2x80x9ccombination therapiesxe2x80x9d of this invention. Combination therapies include therapeutic methods wherein a compound of Formula I of this invention and a Second Agent are administered together as part of the same pharmaceutical composition and to methods wherein these two agents are administered separately, either simultaneously or sequentially in any order.
This invention further provides pharmaceutical kits comprising a compound of Formula I of this invention and a Second Agent. Such kits may hereinafter be referred to as the xe2x80x9ckitsxe2x80x9d of this invention.
Any selective serotonin reuptake inhibitor (SSRI) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term selective serotonin reuptake inhibitor refers to an agent which inhibits the reuptake of serotonin by afferent neurons. Such inhibition is readily determined by those skilled in the art according to standard assays such as those disclosed in U.S. Pat. No. 4,536,518 and other U.S. patents recited in the next paragraph.
Preferred SSRIs which may be used in accordance with this invention include femoxetine, which may be prepared as described in U.S. Pat. No. 3,912,743; fluoxetine, which may be prepared as described in U.S. Pat. No. 4,314,081; fluvoxamine, which may be prepared as described in U.S. Pat. No. 4,085,225; indalpine, which may be prepared as described in U.S. Pat. No. 4,064,255; indeloxazine, which may be prepared as described in U.S. Pat. No. 4,109,088; milnacipran, which may be prepared as described in U.S. Pat. No. 4,478,836; paroxetine, which may be prepared as described in U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196; sertraline, which may be prepared as described in U.S. Pat. No. 4,536,518; sibutramine, which may be prepared as described in U.S. Pat. No. 4,929,629; and zimeldine, which may be prepared as described in U.S. Pat. No. 3,928,369. Fluoxetine is also known as Prozac(copyright). Sertraline hydrochloride, also known as Zoloft(copyright), may be prepared as set forth in U.S. Pat. No. 4,536,518. Sibutramine is also known as Meridia(copyright).
SSRIs are preferably administered in amounts ranging from about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably about 10 mg to about 300 mg per day for an average subject, depending upon the SSRI and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any 3-hydroxy-3-methylglutaryl coenzyme A (HMGxe2x80x94CoA) reductase inhibitor (vastatin) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term 3-hydroxy-3-methylglutaryl coenzyme A (HMGxe2x80x94CoA) reductase inhibitor refers to a pharmaceutical agent which inhibits the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMGxe2x80x94CoA) reductase. This enzyme is involved in the conversion of HMGxe2x80x94CoA to mevalonate, which is one of the steps in cholesterol biosynthesis. Such inhibition is readily determined according to standard assays well known to those skilled in the art.
Preferred vastatins which may be used in accordance with this invention include atorvastatin, disclosed in U.S. Pat. No. 4,681,893, atorvastatin calcium, disclosed in U.S. Pat. No. 5,273,995, cerivastatin, disclosed in U.S. Pat. No. 5,502,199, dalvastatin, disclosed in European Patent Application Publication No. 738,510 A2, fluindostatin, disclosed in European Patent Application Publication No. 363,934 A1, fluvastatin, disclosed in U.S. Pat. No. 4,739,073, lovastatin, disclosed in U.S. Pat. No. 4,231,938, mevastatin, disclosed in U.S. Pat. No. 3,983,140, pravastatin, disclosed in U.S. Pat. No. 4,346,227, simvastatin, disclosed in U.S. Pat. No. 4,444,784 and velostatin, disclosed in U.S. Pat. No. 4,448,784 and U.S. Pat. No. 4,450,171. Especially preferred 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors include atorvastatin, atorvastatin calcium, also known as Liptor(copyright), lovastatin, also known as Mevacor(copyright), pravastatin, also known as Pravachol(copyright), and simvastatin, also known as Zocor(copyright).
Vastatins are preferably administered in amounts ranging from about 0.1 mg/kg to about 1000 mg/kg/day in single or divided doses, preferably about 1 mg/kg/day to about 200 mg/kg/day for an average subject, depending upon the vastatin and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any thiazolidinedione antidiabetic agent may be used in the combination compositions, combination therapies and kits of this invention. The term thiazolidinedione antidiabetic agent refers to a pharmaceutical agent that increases insulin sensitivity in tissues important for insulin action such as adipose tissue, skeletal muscle, and liver.
The following patents exemplify thiazolidinedione antidiabetic agents which can be used in the combination compositions, methods and kits of this invention: U.S. Pat. Nos. 4,340,605; 4,342,771; 4,367,234; 4,617,312; 4,687,777 and 4,703,052. Preferred thiazolidinedione antidiabetic agents include darglitazone, ciglitazone, pioglitazone, also known as Actos(copyright), and rosiglitazone, also known as Avandia(copyright).
Thiazolidinedione antidiabetic agents are preferably administered in amounts ranging from about 0.1 mg/day to about 100 mg/day in single or divided doses, preferably about 0.1 mg/day to about 50 mg/day for an average subject, depending upon the thiazolidinedione antidiabetic agent and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any angiotensin converting enzyme (ACE) inhibitor may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term angiotensin converting enzyme inhibitor refers to a pharmaceutical agent which inhibits angiotensin converting enzyme activity. ACE is involved in the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The activity of ACE inhibitors may readily be determined by methods known to those skilled in the art, including any of the standard assays described in the patents listed below.
Preferred ACE inhibitors include: alacepril, disclosed in U.S. Pat. No. 4,248,883; benazepril, disclosed in U.S. Pat. No. 4,410,520; captopril, disclosed in U.S. Pat. Nos. 4,046,889 and 4,105,776; ceronapril, disclosed in U.S. Pat. No. 4,452,790; delapril, disclosed in U.S. Pat. No. 4,385,051; enalapril, disclosed in U.S. Pat. No. 4,374,829; fosinopril, disclosed in U.S. Pat. No. 4,337,201; imadapril, disclosed in U.S. Pat. No. 4,508,727; lisinopril, disclosed in U.S. Pat. No. 4,555,502; moexipril, disclosed in U.S. Pat. No. 4,344,949; moveltopril, disclosed in Belgian Patent No. 893,553; perindopril, disclosed in U.S. Pat. No. 4,508,729; quinapril, disclosed in U.S. Pat. No. 4,344,949; ramipril, disclosed in U.S. Pat. No. 4,587,258; spirapril, disclosed in U.S. Pat. No. 4,470,972; temocapril, disclosed in U.S. Pat. No. 4,699,905; and trandolapril, disclosed in U.S. Pat. No. 4,933,361.
ACE inhibitors are preferably administered in amounts ranging from about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably about 10 mg to about 300 mg per day for an average subject, depending upon the ACE inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any angiotensin-II receptor (A-II) antagonist may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term angiotensin-II receptor antagonist refers to a pharmaceutical agent that blocks the vasoconstrictor effects of angiotensin II by blocking the binding of angiotensin II to the AT, receptor found in many tissues, (e.g., vascular smooth muscle, adrenal gland). The activity of an A-II antagonist may readily be determined by methods known to those skilled in the art, including any of the standard assays described in the patents listed below.
Preferred A-II antagonists include: candesartan, which may be prepared as disclosed in U.S. Pat. No. 5,196,444; eprosartan, which may be prepared as disclosed in U.S. Pat. No. 5,185,351; irbesartan, which may be prepared as disclosed in U.S. Pat. No. 5,270,317; losartan, which may be prepared as disclosed in U.S. Pat. No. 5,138,069; and valsartan, which may be prepared as disclosed in U.S. Pat. No. 5,399,578. More preferred angiotensin-II receptor antagonists are losartan, irbesartan and valsartan.
A-II antagonists are preferably administered in amounts ranging from about 0.01 mg/kg/day to about 500 mg/kg/day in single or divided doses, preferably about 10 mg to about 300 mg per day for an average subject, depending upon the A-II antagonist and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any y-aminobutyric acid (GABA) agonist may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term y-aminobutyric acid agonist refers to a pharmaceutical agent that binds to GABA receptors in the mammalian central nervous system. GABA is the major inhibitory neurotransmitter in the mammalian central nervous system. The activity of a GABA agonist may readily be determined by methods known to those skilled in the art, including the procedures disclosed n Jassens-dewerebeke, P. et al., Biochem. Pharmacol., 31, 2257-2261 (1982), Loscher, W., Biochem. Pharmacol., 31, 837-842, (1982) and/or Phillips, N. et al., Biochem. Pharmacol., 31, 2257-2261.
Preferred GABA agonists include: muscimol, which may be prepared as disclosed in U.S. Pat. No. 3,242,190; progabide, which may be prepared as disclosed in U.S. 4,094,992; riluzole, which may be prepared as disclosed in U.S. Pat. No. 4,370,338; baclofen, which may be prepared as disclosed in U.S. Pat. No. 3,471,548; gabapentin (Neurontin(copyright)), which may be prepared as disclosed in U.S. Pat. No. 4,024,175; vigabatrin, which may be prepared as disclosed in U.S. Pat. No. 3,960,927; valproic acid, which may be prepared as disclosed in Carraz et al., Therapie, 1965, 20, 419; tiagabine (Gabitril(copyright)), which may be prepared as disclosed in U.S. Pat. No. 5,010,090; lamotrigine (Lamictal(copyright)), which may be prepared as disclosed in U.S. Pat. No. 4,602,017; pregabalin, which may be prepared as disclosed in U.S. Pat. No. 6,028,214; phenytoin (Dilantin(copyright)), which may be prepared as disclosed in U.S. Pat. No. 2,409,754; carbamazepine (Tegretol(copyright)), which may be prepared as disclosed in U.S. Pat. No. 2,948,718; and topiramate (Topamax(copyright)) which may be prepared as disclosed in U.S. Pat. No. 4,513,006; and analogs, derivatives, prodrugs and pharmaceutically acceptable salts of those GABA agonists.
In general, in accordance with this invention, the GABA agonist used in the combinations, pharmaceutical compositions, methods and kits of this invention will be administered in a dosage of about 4 mg/kg body weight of the subject to be treated per day to about 60 mg/kg body weight of the subject to be treated per day, in single or divided doses. However, some variation in dosage will necessarily occur depending upon the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject. In particular, when used as the GABA agonist in this invention, pregabalin will be dosed at about 300 mg to about 1200 mg per day; gabapentin will be dosed at about 600 mg to about 3600 mg per day.
Any glycogen phosphorylase inhibitor (GPI) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of glycogen phosphorylase. Such actions are readily determined by those skilled in the art according to standard assays as described in U.S. Pat. No. 5,988,463.
U.S. Pat. No. 5,988,463, PCT application publication WO 96/39384 and PCT application publication WO96/39385 exemplify GPIs which can be used in the combination compositions, methods and kits of this invention, and refer to methods of preparing those GPIs.
GPIs are preferably administered in amounts ranging from about 0.005 mg/kg/day to about 50 mg/kg/day in single or divided doses, preferably about 0.1 mg/kg to about 15 mg/kg per day for an average subject, depending upon the GPI and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any sorbitol dehydrogenase inhibitor (SDI) may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term sorbitol dehydrogenase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of sorbitol dehydrogenase. Sorbitol dehydrogenase catalyzes the oxidation of sorbitol to fructose.
SDIs are disclosed in commonly assigned U.S. Pat. Nos. 5,728,704, 5,866,578 and PCT application publication WO 00/59510.
The activity of SDIs may be evaluated using the assays and methods disclosed in commonly assigned PCT application publication WO 00/59510 and other assays and methods known by those skilled in the art.
SDIs are preferably administered in amounts ranging from about 0.001 mg/kg/day to about 100 mg/kg/day in single or divided doses, preferably about 0.01 mg/kg to about 10 mg/kg per day for an average subject, depending upon the SDI and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
Any phosphodiesterase type 5 (PDE-5) inhibitor may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term phosphodiesterase type 5 inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or eliminates the enzymatic action of cyclic guanosine monophosphate (cGMP)-specific PDE-5. Such actions are readily determined by those skilled in the art according to assays as described in PCT application publication WO 00/24745.
The following patent publications exemplify phosphodiesterase type 5 inhibitors which can be used in the combination compositions, methods and kits of this invention, and refer to methods of preparing those phosphodiesterase type 5 (PDE-5) inhibitors: PCT application publication WO 00/24745; PCT application publication WO 94/28902; European Patent application publication 0463756A1; European Patent application publication 0526004A1 and European Patent application publication 0201188A2. A preferred phosphodiesterase type 5 inhibitor is sildenafil, which may be prepared as set forth in U.S. Pat. No. 5,250,534. The citrate salt of sildenafil, also known as Viagra(copyright), which may be prepared as disclosed in U.S. Pat. No. 5,955,611, is even more preferred.
PDE-5 inhibitors are preferably administered in amounts ranging from about 5 mg/day to about 500 mg/day in single or divided doses, preferably about 10 mg/day to about 250 mg/day, for an average subject depending upon the PDE-5 inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending on the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any adenosine agonist may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term adenosine agonist refers to any substances and/or agents which pharmacologically affect the cardioprotective effects of ischemic preconditioning by activating adenosine A-3 receptors.
The utility of the adenosine agonists as medical agents in the treatment of cardiac tissue ischemia is demonstrated by the activity of said agonists in conventional preclinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92:912-917 (1995); the isolated heart assay in Tracey, W. R. et al., Cardiovascular Research 33:410-415 (1997), the antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of adenosine agonists can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
Human Adenosine A1 and A3 Receptor Assays
Materials
Full-length human adenosine A1 and A3 receptor cDNA""s subdloned into the eukaryotic expression vector pRcCMV (Invitrogen) were purchased from The Garvan Institute, Sydney, Australia. Chinese hamster ovary (CHO-K1) cells were obtained from the American Type Tissue Culture Collection (Rockville, Md., USA). DMEM and DMEM/F12 culture media and foetal calf serum were obtained from Gibco-BRL (Grand Island, N.Y., USA). The Al/A3 adenosine receptor agonist N6-(4-amino-3-[1251]iodobenzyl)adenosine (125I-ABA) was prepared by New England Nuclear (Boston, Mass., USA). Adenosine deaminase (ADA) was obtained from Boehringer Mannheim (Indianapolis, Ind., USA). The phosphodiesterase inhibitor RO-20-1724 was obtained from Research Biochemicals International (Natick, Mass., USA).
Expression of Human Adenosine Al and A3 Receptors
For stable expression studies, adenosine receptor A1 and A3 expression plasmids (20 xcexcg) are transfected into CHO-KL cells, or HEK 293s cells, respectively, grown in DMEM/F12 (CHO) or DMEM (HEK 293s), with 10% foetal calf serum media, using a calcium phosphate mammalian cell transfection kit (5 Prime-3 Prime). Stable transfectants are obtained by selection in complete media containing 500 xcexcg/ml (CHO) or 700 xcexcg/ml (HEK 293s) active neomycin (G418) and screened for expression by [125I ]-ABA binding.
Receptor Membrane Preparation
Cells stably expressing either human A1 or human A3 receptors are collected by centrifugation at 300xc3x97g for 5 minutes, the supernatant is discarded and the cell pellet is resuspended in cell buffer consisting of (mmoles/L): HEPES (10), MgCl2 (5), PMSF (0.1), bacitracin (100 xcexcg/ml), leupeptin (10 xcexcg/ml), DNAse I (100 xcexcg/ml), ADA (2 U/ml), pH 7.4. Crude cell membranes are prepared by repeated aspiration through a 21 gauge needle, collected by centrifugation at 60,000xc3x97g for 10 minutes and stored in cell buffer at xe2x88x9280xc2x0 C.
Estimation of Compound Binding Affinity Constants (Ki)
Receptor membranes are resuspended in incubation buffer consisting of (mmoles/L): HEPES (10), EDTA (1), MgCl2 (5), pH 7.4. Binding reactions (10-20 xcexcg membrane protein) are carried out for one hour at room temperature in 250 xcexcl incubation buffer containing 0.1 nM of 125I-ABA (2200 Ci/mmol) and increasing concentrations of compound (0.1 nM-30 xcexcM). The reaction is stopped by rapid filtration with ice-cold PBS, through glass fibre filters (presoaked in 0.6% polyethylenimine) using a Tomtec 96-well harvester (Orange, Conn., USA). Filters are counted in a Wallac Microbeta liquid scintillation counter (Gaithersberg, Md., USA). Nonspecific binding is determined in the presence of 5 xcexcM I-ABA. Compound inhibitory constants (Ki) are calculated by fitting binding data via nonlinear least squares regression analysis to the equation: % Inhibition=100/[1+(10C/10X)D], where X=log [compound concentration], C (IC50)=log [compound concentration at 50% inhibtion], and D=the Hill slope. At the concentration of radioligand used in the present study (10 fold  less than KD), IC50=Ki.
Assessment of Human Adenosine A3 Receptor Agonist Activity
Adenosine A3 agonist activity is assessed by compound inhibition of isoproterenol-stimulated cAMP levels. HEK293s cells stably transfected with human A3 receptors (as described above) are washed with Phosphate Buffered Saline (PBS) (Ca/Mg-free) and detached with 1.0 mM EDTA/PBS. Cells are collected by centrifugation at 300xc3x97g for 5 minutes and the supernatant discarded. The cell pellet is dispersed and resuspended in cell buffer (DMEMIF12 containing 10 mM HEPES, 20 xcexcM RO-20-1724 and 1 U/ml ADA). Following preincubation of cells (100,000/well) for 10 min at 37xc2x0 C., 1 xcexcM isoproterenol, with or without increasing concentrations (0.1 nM-300 nM) test compound, and the incubation is continued for 10 min. Reactions are terminated by the addition of 1.0 N HCl followed by centrifugation at 2000xc3x97g for 10 minutes. Sample supernatants (10 xcexcl) are removed and cAMP levels determined by radioimmunoassay (New England Nuclear, Boston, Mass., USA). The basal and control-isoproterenol-stimulated cAMP accumulation (pmol/ml/100,000 cells) are routinely 3 and 80, respectively. Smooth curves are fitted to the data via nonlinear least squares regression analysis to the equation: % isoproterenol-stimulated cAMP=100/[1+(10X/10C)D], where X=log [compound concentration], C (IC50)=log [compound concentration at 50% inhibition], and D=the Hill slope.
The therapeutic effects of the compounds of this invention in preventing heart tissue damage resulting from an ischemic insult can be demonstrated in vitro along lines presented in Tracey et al. (Cardiovasc. Res., 33:410-415, 1997).
The following patent publications exemplify adenosine agonists which can be used in the combination compositions, methods and kits of this invention, and refer to methods of preparing those adenosine agonists: U.S. Pat. Nos. 5,604,210; 5,688,774; 5,773,423; J. Med. Chem. 1994, 37, 636-646; J. Med. Chem. 1995, 38,1174-1188; J. Med. Chem. 1995, 38, 1720-1735.
U.S. Pat. No. 5,817,760 discloses recombinant human adenosine receptors A1, A2a, A2b, and A3 which were prepared by cDNA cloning and polymerase chain reaction techniques. The recombinant adenosine receptors can be utilized in an assay to identify and evaluate entities that bind to or enhance binding to adenosine receptors.
Adenosine agonists are preferably administered in amounts ranging from about 0.001 mg/kg/day to about 100 mg/kg/day, for an average subject depending upon the adenosine agonist and the route of administration. An especially preferred dosage is about 0.01 mg/kg/day to about 50 mg/kg/day of an adenosine agonists. However, some variation in dosage will necessarily occur depending upon the condition of the subject being treated. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
Any NHE-1 inhibitor may be used as the Second Agent in the combination compositions, combination therapies and kits of this invention. The term NHE-1 inhibitor refers to compounds which inhibit the sodium/proton (Na+/H+) exchange transport system and hence are useful as a therapeutic or prophylactic agent for diseases caused or aggravated by the acceleration of the sodium/proton (Na+/H+) exchange transport system, for example, cardiovascular diseases [e.g., arteriosclerosis, hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due to myocardial infarction, myocardial stunning, myocardial dysfunction, arrhythmia after PTCA or after thrombolysis, etc.), angina pectoris, cardiac hypertrophy, myocardial infarction, heart failure (e.g. congestive heart failure, acute heart failure, cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock (e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases (e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal failure, etc.) organ disorders associated with ischemia or ischemic reperfusion [e.g. heart muscle ischemic reperfusion associated disorders, acute renal failure, or disorders induced by surgical treatment such as coronary artery bypass grafting (CABG) surgeries, vascular surgeries, organ transplantation, non-cardiac surgeries or percutaneous transluminal coronary angioplasty (PTCA)], cerebrovascular diseases (e.g. ischemic stroke, hemorrhagic stroke, etc.), cerebro ischemic disorders (e.g. disorders associated with cerebral infarction, disorders caused after cerebral apoplexy as sequelae, or cerebral edema. NHE-1 inhibitors can also be used as an agent for myocardial protection during coronary artery bypass grafting (CABG) surgeries, vascular surgeries, percutaneous transluminal coronary angioplasty (PTCA), PTCI, organ transplantation, or non-cardiac surgeries.
The utility of the combination of compounds of the present invention with NHE-1 inhibitors as medical agents in the treatment of diseases, such as are detailed herein in mammals (e.g. humans) for example, myocardial protection during surgery or mycardial protection in patients presenting with ongoing cardiac or cerebral ischemic events or chronic cardioprotection in patients with diagnosed coronary heart disease, or at risk for coronary heart disease, cardiac dysfunction or myocardial stunning is demonstrated by the activity of said combination in conventional preclinical cardioprotection assays [see the in vivo assay in Klein, H. et al., Circulation 92:912-917 (1995); the isolated heart assay in Scholz, W. et al., Cardiovascular Research 29:260-268 (1995); the antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro and in vivo assays described below. Such assays also provide a means whereby the activities of the compounds of formula I of this invention can be compared with the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in mammals, including humans, for the treatment of such diseases.
The following patent publications exemplify NHE-1 inhibitors which can be used in the combination compositions, methods and kits of this invention, and refer to methods of preparing those NHE-1 inhibitors U.S. Pat. No. 5,698,581, European Patent Application Publication No. EP 803 501 A1, International Patent Application Publication Nos. WO 94/26709 and PCT/JP97/04650.
Preferred NHE-1 inhibitors include compounds of the formula NHE, 
a prodrug thereof or a pharmaceutically acceptable salt of said compound or of said prodrug, wherein
Z in the compound of formula NHE is carbon connected and is a five-membered, diaza, diunsaturated ring having two contiguous nitrogens, said ring optionally mono-, di-, or tri-substituted with up to three substituents independently selected from R1, R2 and R3;
or
Z in the compound of formula NHE carbon connected and is a five-membered, triaza, diunsaturated ring, said ring optionally mono- or di-substituted with up to two substituents independently selected from R4 and R5;
wherein R1, R2, R3, R4 and R5 in the compound of formula NHE are each independently hydrogen, hydroxy-(C1-C4)alkyl, (C1-C4)alkyl, (C1-C4)alkylthio, (C3-C4)cycloalkyl, (C3-C7)cycloalkyl(C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkoxy(C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, M or M(C1-C4)alkyl, any of said previous (C1-C4)alkyl moieties optionally having from one to nine fluorines; said (C1-C4)alkyl or (C3-C4)cycloalkyl optionally mono-or di-substituted independently with hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl; and said (C3-C4)cycloalkyl optionally having from one to seven fluorines;
wherein M in the compound of formula NHE is a partially saturated, fully saturated or fully unsaturated five to eight membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen, or, a bicyclic ring consisting of two fused partially saturated, fully saturated or fully unsaturated three to six membered rings, taken independently, optionally having one to four heteroatoms selected independently from nitrogen, sulfur and oxygen;
said M in the compound of formula NHE is optionally substituted, on one ring if the moiety is monocyclic, or one or both rings if the moiety is bicyclic, on carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, wherein one of R6, R7 and R8 is optionally a partially saturated, fully saturated, or fully unsaturated three to seven membered ring optionally having one to three heteroatoms selected independently from oxygen, sulfur and nitrogen optionally substituted with (C1-C4)alkyl and additionally R6, R7 and R are optionally hydroxy, nitro, halo, (C1-C4)alkoxy, (C1-C4)alkoxycarbonyl, (C1-C4)alkyl, formyl, (C1-C4)alkanoyl, (C1-C4)alkanoyloxy, (C1-C4)alkanoylamino, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C5-C7)cycloalkenyl,
wherein said (C1-C4)alkoxy, (C1-C4)alkyl, (C1-C7)alkanoyl, (C1-C4)alkylthio, mono-N- or di-N,N-(C1-C4)alkylamino or (C3-C7)cycloalkyl R6, R7 and R8 substituents are optionally mono- substituted independently with hydroxy, (C1-C4)alkoxycarbonyl, (C3-C7)cycloalkyl, (C1-C4)alkanoyl, (C1-C4)alkanoylamino, (C1-C4)alkanoyloxy, (C1-C4)alkoxycarbonylamino, sulfonamido, (C1-C4)alkylsulfonamido, amino, mono-N- or di-N,N-(C1-C4)alkylamino, carbamoyl, mono-N- or di-N,N-(C1-C4)alkylcarbamoyl, cyano, thiol, nitro, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl or mono-N- or di-N,N-(C1-C4)alkylaminosulfonyl or optionally substituted with one to nine fluorines.
Especially preferred NHE-1 inhibitors include [1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(indazol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine; [1-(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(1-methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; 1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine; [1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine; [5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine; [1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine; [5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1 H-pyrazole-4-carbonyl]guanidine; [1-(2,5-dichlorophenyl)-5-cyclopropyl-1 H-pyrazole-4-carbonyl]guanidine; [1-(2,3-dichlorophenyl)-5-cyclopropyl-1 H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-aminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-fluoro-6-trifluoromethylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1 H-pyrazole-4-carbonyl]guanidine; [1-(2-chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-trifluoromethyl-4-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine; [1-(2-chlorophenyl)-5-methyl-1H-pyrazole-4-carbonyl]guanidine; [5-methyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine; [5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine; [5-cyclopropyl-l-(2,6-dichlorophenyl)-1 H-pyrazole-4-carbonyl]guanidine or or a pharmaceutically acceptable salt thereof.
The preferred and especially preferred NHE-1 inhibitors disclosed in the above two paragraphs can be prepared according to methods set forth in International Patent Application No. PCT/IB99/00206.
NHE-1 inhibitors are preferably administered in amounts ranging from about 0.001 mg/day to about 100 mg/day, for an average subject depending upon the NHE-1 inhibitor and the route of administration. However, some variation in dosage will necessarily occur depending upon the condition of the subject being treated. An especially preferred dosage contains about 0.01 to 50 mg/day of said NHE-1 inhibitor. The individual responsible for dosing will, in any event, determine the appropriate dose for the individual subject.
As used herein, the term xe2x80x9ceffective amountxe2x80x9d refers to an amount of compound or compounds of the present invention which is capable of inhibiting or preventing diabetic complications and/or cardiac tissue ischemia, herein described. The terms xe2x80x9cinhibitxe2x80x9d or xe2x80x9cinhibitingxe2x80x9d refers to prohibiting, treating, alleviating, ameliorating, halting, restraining, slowing or reversing the progression, or reducing the severity of a complication resulting from diabetes in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compounds administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgement of the prescribing physician. Thus, because of patient to patient variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the patient. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.
In the aspects of this invention related to therapeutic methods of treating or preventing diabetic complications wherein a compound of Formula I of this invention and a Second Agent are administered together as part of the same pharmaceutical composition and to methods wherein these two agents are administered separately, the appropriate dosage regimen, the amount of each dose administered and the intervals between doses of the active agents will again depend upon the compound of Formula I of this invention and the Second Agent being used, the type of pharmaceutical compositions being used, the characteristics of the subject being treated and the severity of the condition or conditions.
Administration of the compounds and pharmaceutical compositions of this invention may be performed via any method which delivers a compound or composition of this invention preferentially to the desired tissue (e.g., nerve, kidney, lens, retina and/or cardiac tissues). These methods include oral routes, parenteral, intraduodenal routes, etc, and may be administered in single (e.g., once daily) or multiple doses or via constant infusion.
The pharmaceutical compositions of this invention may be administered to a subject in need of treatment by a variety of conventional routes of administration, including orally, topically, parenterally, e.g., intravenously, rectally, subcutaneously or intramedullary. Further, the pharmaceutical compositions of this invention may be administered intranasally, as a suppository or using a xe2x80x9cflashxe2x80x9d formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water.
The compounds of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or diluents, in either single or multiple doses. Suitable pharmaceutical carriers, vehicles and diluents include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents. The pharmaceutical compositions formed by combining the compounds of this invention and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and/or calcium phosphate may be employed along with various disintegrants such as starch, alginic acid and/or certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and/or acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active pharmaceutical agent therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and/or combinations thereof.
For parenteral administration, solutions of the compounds of this invention in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, the sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
Generally, a composition of this invention is administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from gastrointestinal disorders or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending physician.
Buccal administration of a composition of this invention may take the form of tablets or lozenges formulated in a conventional manner.
For intranasal administration or administration by inhalation, the compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of a compound of this invention. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound or compounds of the invention and a suitable powder base such as lactose or starch.
For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, are prepared.
Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Reminciton""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).
In the aspects of this invention related to the combination compositions, wherein the compositions contain an amount of both a compound of Formula I of this invention and a Second Agent, the amount of each such ingredient may independently be 0.0001%-95% of the total amount of the composition, provided, of course, that the total amount does not exceed 100%. In any event, the composition or formulation to be administered will contain a quantity of each of the components of the composition according to the invention in an amount effective to treat the disease/complications of the subject being treated.
Since the present invention has an aspect that relates to the treatment of the disease/complications described herein with a combination of active ingredients which may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. The kit comprises two separate pharmaceutical compositions: a compound of Formula I a prodrug thereof or a pharmaceutically acceptable salt of such compound or prodrug and a Second Agent as described above. The kit comprises a container for containing the separate compositions such as a divided bottle or a divided foil packet. Typically the kit comprises directions for the administration of the separate components. The kit form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), are administered at different dosage intervals, or when titration of the individual components of the combination is desired by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows xe2x80x9cFirst Week, Monday, Tuesday, . . . etc . . . Second Week, Monday, Tuesday, . . .xe2x80x9d etc. Other variations of memory aids will be readily apparent. A xe2x80x9cdaily dosexe2x80x9d can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a compound of Formula I of this invention can consist of one tablet or capsule while a daily dose of the Second Agent can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
In another specific embodiment of the invention, a dispenser designed to dispense the daily doses one at a time in the order of their intended use is provided. Preferably, the dispenser is equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that has been dispensed. Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.
The journal articles and scientific references, patents and patent application publications cited above are wholly incorporated herein by reference.
General Experimental Procedures
Melting points were determined on a Thomas-Hoover capillary melting point apparatus, and are uncorrected. Low-resolution mass spectra were obtained under thermospray (TS) conditions on a Fisons (now Micromass) Trio 1000 Mass Spectrometer (Micromass Inc., Beverly, Mass.), under chemical-ionization (Cl) conditions on a Hewlett Packard 5989A Particle Beam Mass Spectrometer (Hewlett Packard Co., Palo Alto, Calif.), or under atmospheric pressure chemical ionization (APCI) on a Fisons (now Micromass) Plafform II Spectrometer.